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Biomedical subjects

R H Waring

Publications and source records attributed to R H Waring.

At least 55 records · Page 3Linked to original sources
PubMed1998

Fate of thianthrene in rat.

1. Radiolabelled thianthrene was administered by gavage (200 mg/kg body weight) to the adult female Wistar rat following an overnight fast. 2. Faeces was the major route of excretion of radioactivity (62%) with substantial amounts still being voided during the third day (17%). Urinary elimination (26%) peaked during the second and third days and a small amount of radioactivity (7%) remained within the carcass after 4 days. Distribution studies showed that the majority of the compound remained within the gastrointestinal tract. 3. Metabolism was limited to ring hydroxylation with subsequent conjugate formation. Oxidation of the sulphur to form the monosulphoxide and disulphoxide derivatives also occurred. No evidence for cleavage of the ring structures was observed.

Administration, Oral↗
PubMed1998

Inhibition of phenolsulphotransferase by salicylic acid: a possible mechanism by which aspirin may reduce carcinogenesis.

BACKGROUND: Recent epidemiological evidence has shown that chronic use of aspirin decreases susceptibility to bowel cancer. Animal studies have shown that sulphotransferase inhibitors coadministered with sulphation activated carcinogens dramatically reduce the incidence of cancer. AIMS: To investigate the effect of the main aspirin breakdown product, salicylic acid, on the P and M isoforms of phenolsulphotransferase from human platelets and colonic mucosa. METHODS: Platelets were obtained from healthy blood donors and isolated within 24 hours after donation. Samples of colonic mucosa were obtained at resection for non-malignant disease. Phenolsulphotransferase activity was measured in cellular homogenates using a standard radiolabelling assay. RESULTS: Salicylic acid consistently and selectively inhibited the P form of phenolsulphotransferase at subtherapeutic concentrations in both tissue samples. A 50% inhibition of sulphation by the P phenolsulphotransferase occurred at salicylic acid concentrations of about 40 and 130 microM in platelets and bowel mucosa respectively. M phenolsulphotransferase was virtually unaffected by salicylic acid up to a concentration of 1.5 mM (the therapeutic plasma concentration for salicylates when treating rheumatoid arthritis is about 1-2 mM). CONCLUSION: The action of salicylic acid on P phenolsulphotransferase, by preventing the excessive activation of carcinogens, is a possible additional pathway by which aspirin can reduce cancer risk.

Aged↗
PubMed1997

Platelet sulphotransferase activity, plasma sulphate levels and sulphation capacity in patients with migraine and tension headache.

Activity of both the M- and P-forms of sulphotransferase (ST) was measured in platelets from patients with migraine, tension headache and controls. Mean PST values were 0.065 +/- 0.023 and 0.057 +/- 0.052 nmol/mg protein/min for migraine patients with and without aura. The corresponding values for tension headache and controls were 0.122 +/- 0.059 and 0.127 +/- 0.093 nmol/mg protein/min respectively (p < 0.05). Mean MST values were not different for any of the groups, and MST and PST activities measured in two patients during a migraine attack were not significantly altered from baseline levels. Mean plasma inorganic sulphate concentrations and paracetamol metabolites were not significantly different in any of the groups studied. The results suggest that PST activity may be a factor in the aetiology of migraine.

Acetaminophen↗
PubMed1996

Human metabolism of paracetamol (acetaminophen) at different dose levels.

Urine (0-24 h) was collected from five subjects on separate occasions following the ingestion of paracetamol at five different dose levels (500, 750, 1000, 1250, 1500 mg) which spanned the normal therapeutic range. The major urinary metabolites were sulphuric and glucuronic acid conjugates which together accounted for around 50% of the administered dose. Unchanged paracetamol excretion was low (5-20%). This situation was similar over the entire dose range. These findings are discussed in relation to previous single dose studies reported in the literature.

Acetaminophen↗
PubMed1996

Dietary modulation of human platelet phenolsulphotransferase activity.

1. The mammalian phenolsulphotransferase enzymes are known to play a major role in both the detoxification and possibly the activation of pre-carcinogenic phenols and aromatic amines. 2. Vegetable cytosol preparations were tested in vitro for their ability to affect the sulphation of two reference compounds (rho-nitrophenol and dopamine, which are selective substrates for the phenol and monoamine forms of phenolsulphotransferase respectively), and to act as substrates for the enzymes in comparison with the same reference compounds. 3. The majority of cytosols greatly decreased (> 80%) the sulphation of either or both the reference compounds. This effect may have been due to either enzyme inhibition or substrate binding. 4. Whereas some of the cytosols were sulphated under the assay conditions, most were not. Additionally, it was found that a cytosol that decreased the sulphation of the two reference compounds was not necessarily poorly sulphated itself. 5. It is concluded that dietary factors have the potential to play a major role in modulating the sulphation detoxification pathway, and have wide ranging implications with regard to adverse drug reactions.

Arylsulfotransferase↗
PubMed1995

Toxicity of sulphur-containing compounds to neuronal cell lines.

Cysteine and its metabolites cysteine sulphinic acid (CSA) and taurine (TA) were shown to be toxic to human and rat neuronal cell lines. However, the mechanisms of action of CSA and TA appeared to be different. As MND/ALS patients have high plasma and CSF cysteine levels, they may have increased levels of neurotoxins in vivo, since cysteine was more toxic than CSA in the assay system used. Cysteic acid, homocysteic acid, BMAA and BOAA were also toxic to the cell lines used.

Animals↗
PubMed1995

Sulphoxidation and sulphation capacity in patients with primary biliary cirrhosis.

We have previously reported an association of impaired S-oxidation with primary biliary cirrhosis. In order to confirm and further define this relationship, we retested S-oxidation capacity via three metabolic pathways and sulphation capacity via a fourth pathway. Metabolism of S-carboxymethyl-L-cysteine is polymorphic -20% of healthy individuals being poor S-oxidisers. We found 26% with primary biliary cirrhosis were poor S-oxidisers, compared with 36% with other liver disease and 25% of healthy controls. Differences were not statistically significant. S-oxidation of ranitidine is dependent upon flavin mono-oxygenases. We showed a non-significant trend toward less S-oxide in primary biliary cirrhosis and other liver disease, compared with healthy controls, with no significant difference between disease groups. Conversion of cysteine to sulphate depends predominantly on cysteine dioxygenase. Impaired activity may be reflected by decreased plasma sulphate and elevated cysteine. We found that the plasma cysteine: sulphate ratio was significantly elevated not only in primary biliary cirrhosis (p < 0.0001), but also in other liver disease (p < 0.0001), compared with healthy individuals. Sulphation capacity was studied by analysing paracetamol metabolism. Paracetamol sulphate and sulphate: glucuronide ratio were reduced in primary biliary cirrhosis compared with normal individuals, (p < 0.05). A trend towards less sulphate in primary biliary cirrhosis compared other liver disease was not significant (p = 0.42). We conclude that although sulphation and some sulphoxidation pathways are impaired in primary biliary cirrhosis, we can currently find no evidence to substantiate the hypothesis that primary biliary cirrhosis is a disease specifically associated with poor S-oxidation, as assessed via these metabolic pathways.

Acetaminophen↗
PubMed1995

The genetic origin of responses to drugs.

Individual variation in drug metabolism has been extensively investigated. Population studies have shown that there is a wide range in metabolising ability for all detoxification pathways; the distributions may be unimodal (Gaussian) or polymodal, with subsets of individuals who differ from the majority. These may be poor metabolisers (PM) or extensive metabolisers (EM). In many cases, these phenotypes can be linked with the genotype. Frequently the PM phenotype is more susceptible to drug toxicity, while the EM phenotype requires increased dosage for therapeutic benefit. In some cases, phenotypes or genotypes appear to have increased susceptibility to clinical disease. These ideas are discussed for the cytochrome P-450 isozymes, FMO system, cysteine dioxygenase-linked oxidations, glucuronidation, sulphation, acetylation, glutathione conjugation and methylation pathways.

Acetylation↗
PubMed1995

Carbon isotope variation in Douglas-fir foliage: improving the delta(13)C-climate relationship.

The natural abundance of stable carbon isotopes in the annual rings of forest trees is used as a tracer of environmental changes such as climate and atmospheric pollution. Although tree-ring delta(13)C varies by about 2 per thousand from year to year, variability within the foliage can be as high as 6 per thousand. Recent studies have shown that branch length affects stomatal response, which influences the integrated foliar delta(13)C signal. To improve the ability of delta(13)C to predict climate differences, we examined the relationship between branch length and foliar delta(13)C in Pseudotsuga menziesii (Mirb.) Franco from four sites across a steep climate gradient in Oregon. The transect spanned the boundary between the ranges of the coastal variety, P. menziesii var. menziesii (three sites), and the Rocky Mountain variety, P. menziesii var. glauca (one site). At the most maritime site, branch length explained 76% of within-site variation of 5 per thousand, whereas at the harshest site, branch length accounted for only 15% of this variation. We considered the possibility that cavitation in the water-conducting xylem obscures the branch length effect in the harsher climates. Cavitation, as measured by dye perfusion, was most extensive at sites where the branch length effect in the coastal variety was weakest. Trees at the site with the most substantial cavitation displayed seasonal xylem refilling. Branch length standardization significantly improved the relationship between delta(13)C and climate. With standardization to constant length, delta(13)C values were significantly related to the degree that climatic variables, as modeled with a forest growth simulation model, constrain transpiration (R(2) = 0.69, P < 0.0001). Without standardization, the R(2) was 0.27. We conclude that sampling standard length branches or tree rings from trees of similar shape and size is desirable when seeking correlations between isotopic composition and climate.

Journal Article↗
PubMed1994

Pathways of cysteine metabolism in MND/ALS.

Analysis of plasma from MND/ALS patients has shown no significant differences in metabolism of cysteine derivatives, although a sub-set of the population has raised glutamate values. Cysteine dioxygenase was found to have reduced activity in vitro, consistent with previous findings of a high plasma cysteine/sulphate ratio.

Adult↗
PubMed1994

The adverse influence of pregnancy upon sulphation: a clue to the pathogenesis of intrahepatic cholestasis of pregnancy?

Sulphation of oestrogens and monohydroxy bile acids is important in attenuating their cholestatic potential. Thus, impairment of sulphation could lead to retention of cholestatic compounds and precipitate intrahepatic cholestasis in susceptible individuals. We tested the hypothesis that such a mechanism may be involved in the pathogenesis of intrahepatic cholestasis of pregnancy. In vivo and in vitro assessment of sulphation capacity was performed in patients with cholestasis of pregnancy, compared with control females on and off the oestrogen-containing oral contraceptive pill and control individuals during normal pregnancy and post partum, to assess the influence of high oestrogen states upon this metabolic pathway. During in vivo studies utilising paracetamol as a metabolic probe, the proportion of paracetamol sulphate and sulphate: glucuronide ratio were decreased in those with elevated oestrogens, whether the rise in oestrogens was endogenous, in pregnancy (paracetamol sulphate p < 0.05; paracetamol sulphate:glucuronide ratio p < 0.01), or exogenous, with the contraceptive pill (paracetamol sulphate p = 0.2; paracetamol sulphate:glucuronide ratio p < 0.001). In vitro, platelet sulphotransferase activity was measured, utilising phenol as substrate. Sulphotransferase activity decreased during pregnancy compared with repeat measurements post partum (p < 0.005) and compared with non-pregnant individuals (p < 0.05). In conclusion, we have shown that elevated oestrogens are associated with significant impairment in sulphation capacity. An imbalance of sulphation with glucuronidation provoked by high circulating oestrogen levels may be contributory in the pathogenesis of cholestasis of pregnancy.

Acetaminophen↗
PubMed1994

Plasma cysteine and sulphate levels in patients with cirrhosis of the liver.

1. Fasting levels of plasma cysteine, plasma sulphate and the plasma cysteine/sulphate ratio were measured in patients with primary biliary cirrhosis and compared with those in patients with other liver disease, general intensive therapy unit patients and healthy subjects. 2. Plasma cysteine was significantly elevated in patients with primary biliary cirrhosis (median 0.364 nmol/mg of protein, P < 0.0001) and patients with other liver disease (median 0.445 nmol/mg of protein, P < 0.0001), compared with healthy control subjects (median 0.125 nmol/mg of protein) and increased progressively with the severity of liver disease. Plasma cysteine was also elevated in intensive therapy unit patients (median 1.564 nmol/mg of protein) compared with healthy control subjects (P < 0.0001) and patients with other liver disease (P < 0.0001). 3. Plasma sulphate was reduced significantly only in patients with primary biliary cirrhosis (median 0.822 nmol/mg of protein) compared with healthy control subjects (median 1.37 nmol/mg of protein, P < 0.05). There was no significant difference in plasma sulphate between disease groups. 4. The plasma cysteine/sulphate ratio was significantly elevated in patients with primary biliary cirrhosis (median 0.448, P < 0.0001) and patients with other liver diseases (median 0.394, P < 0.0001) compared with healthy control subjects (median 0.095). The ratio was also elevated in intensive therapy unit patients (median 1.650, P < 0.0001) compared with healthy control subjects and liver disease groups (P < 0.0001). 5. In conclusion, cysteine rises in primary biliary cirrhosis and other forms of liver disease. This effect is not specific to liver disease, since cysteine is elevated in an heterogeneous group receiving intense care.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Variation in foliar delta(13)C values within the crowns of Pinus radiata trees.

Although herbaceous species generally show little within plant variation in delta(13)C, trees show large spatial and temporal differences. We found that the aspect of exposure and branch length accounted for up to 6 per thousand delta(13)C difference within the foliage of individual trees of Pinus radiata D. Don. The foliage on branches 0.5 m in length was as much as 4 per thousand more depleted in (13)C than foliage on 10-m long branches, and an additional 2 per thousand more depleted on the shaded side than on the exposed side. We confirmed that on clear days, relative branch hydraulic conductivity, defined as the ratio of transpiration to the water potential gradient, was much higher in short branches than in long branches. Stomatal conductance remained high in foliage on short branches during the day, whereas it declined progressively in long-branch foliage under similar conditions. These differences were sufficient to explain the observed variation in delta(13)C in foliage on long and short branches.

Journal Article↗
PubMed1994

Circadian rhythms of paracetamol metabolism in healthy subjects; a preliminary report.

Paracetamol was used as a "probe" drug to study the circadian rhythms of metabolite ratios in man. Paracetamol was orally administered to six volunteers at different times of day, 0-8 h and 8-24 h urine samples being measured for sulphate and glucuronide formation. Results showed a wide interindividual variation in paracetamol metabolite excretion among the six subjects. However, when a 500 mg dose was administered, free paracetamol excretion was minimal when the dose was given at 12.00 h and maximal when given at 20.00 h for the 0-8 h collection period. Sulphate excretion rose slightly at night and decreased gradually during the day. Glucuronide excretion was greatest with drug administration at 16.00 h and least if paracetamol was ingested at 08.00 h. The 8-24 h profiles were roughly similar. At a higher dose (1500 mg), free paracetamol excretion showed a minimum from dosing at 20.00 h and a maximum from dosing at 24.00 h in both 0-8 h and 8-24 h collections, while the sulphate conjugate peaked for doses at 20.00 h and 8.00 h with collections at 0-8 h and 8-24 h respectively. The glucuronide conjugate was maximal for paracetamol administration at 16.00 h for both 0-8 h and 8-24 h collections. There appears to be a 12 hour phase variation in excretion; this may result from circadian rhythms in absorption and enzyme activities. These parameters may also affect metabolism at higher dose levels, so that the hepatotoxicity of paracetamol could vary with the time of dose.

Acetaminophen↗